Method for nuclear magnetic resonance imaging using deuterum as a contrast agent

ABSTRACT

A method for in vivo NMR imaging of the blood vessels and organs of a patient characterized by using a dark dye-like imaging substance consisting essentially of a stable, high-purity concentration of D 2  O in a solution with water.

The U.S. Government has rights in this invention pursuant to ContractNumber DE-ACO2-76CHOOO16, between the U.S. Department of Energy andAssociated Universities, Inc.

The invention relates to a method for in vivo nuclear magnetic resonance(NMR) in which an image enhancing solution is injected into the patientand, more particularly relates to the use of deuterium oxide mixed withwater to form such an image enhancing solution.

BACKGROUND OF THE INVENTION

It is well known that heavy water or deuterium oxide (D₂ O, or 2H₂ O) isuseful in nuclear magnetic resonance (NMR) spectrographic studies, suchas those now widely used in biochemical research and in developing newapplications for clinical research. An example of such prior art usageis in the measurement of total body water as it is associated withevaluations of acute and chronic alterations in hydration that can becaused by a variety of illnesses. In such methodology, the NMR signal ofD₂ O, or of a D₂ O/H₂ O solution, appears at a frequency that isdistinctly different from all other frequencies of deuterium belongingto any molecular fragment, therefore an accurate estimation of D₂ O inbiological fluids is permitted. Such NMR spectroscopy methods are not,however, useful in providing in vivo NMR imaging of blood vessels andorgans such as the heart, kidneys, liver, etc. of a patient.

There have been a number of earlier studies of the affect of heavy wateron mammals. Theose studies involve either the ingestion of heavy waterby the mammals, or occasionally a subcutaneous injection of heavy waterinto animals has been analyzed. So far as the present inventors areaware, those earlier studies did not involve any use of NMR imaging inconnection with the ingestion or injection of heavy water into a livingmammal patient.

In order to be useful for in vivo NMR imaging, a suitable imaging dyematerial must not resonate at the frequency of water hydrogen, and thedye material must not have an adverse affect on the patient's organsthat are to be imaged with the method. In particular, the dye solutionmust be usable in a sufficient concentration for it to have a desirablelevel of effect on the NMR image. Thus, the use of solutions containingvarious radionuclides or other toxic substances are either severelylimited or precluded from use as NMR imaging dyes for in vivoapplications.

SUMMARY OF THE INVENTION

A method of in vivo nuclear magnetic resonance imaging is provided inwhich a stable, non-toxic deuterium isotope, in the form of D₂ O, isused as a dye-like agent to enhance clinical NMR images of blood vesselsand organs of a patient.

OBJECTS OF THE INVENTION

An object of the invention is to provide a method for in vivo NMRimaging of the vessels and organs of a patient by using an isosmoticsolution of high purity D₂ O to act as a dye-like agent at the frequencyof H-1 resonance when the solution is injected via a catheter into ablood vessel of a patient who is exposed to the magnetic field of an NMRsystem.

Another object of the invention is to provide an in vivo NMR imagingprocess that utilizes a non-toxic solution that appears as a darkdye-like agent when exposed to nuclear resonance.

A further object of the invention is to provide an in vivo NMR imagingmethod that uses a stable, radiation-free dye-like appearing imagingagent such as a suitably concentrated solution of high purity D₂ O(consisting of more than 99.0% by weight D₂ O).

Further objects and advantages of the invention will become apparent tothose skilled in the art from the description of it that follows.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred form of the present invention, a NMR imaging dye-likeagent (sometimes called a contrast agent) is prepared for in vivoinjection into a patient whose blood vessels or organs are to beanalyzed. It has been found that in order to produce a suitably dark NMRimage, an isosmotic solution of high purity D₂ O and water, having aratio of D₂ O/H₂ O equal to at least 99.00% by weight D₂ O must be usedin our method. We have found that the deuterium (D) nuclei emit nosignal at the frequency of the H-1 resonance of an NMR system,accordingly, the D₂ O in our novel imaging agent appears as a dark dyewhen it is injected in vivo into a patient's blood vessel and exposed tothe magnetic field of an NMR system. Thus, as blood circulates throughthe vessel and organs of a patient, the dye-like agent dilutes as itmoves through the arteries into the organs, thereby affording clear NMRimages that are useful in studying such flow and the related vessels andorgans.

Because the D₂ O solution used in our method is free of tritium, and hasno toxic effects, it can be safely used as a dye-like agent for in vivoimaging of blood vessels and organs. Accordingly, this method mayreplace the current use of radioisotopes such as Tl-201 and Tc-99m invarious in vivo analyses, such as the assessment of the hypoperfused andnecrotic myocardium and stress-related perfusion clinical examinations.

In practicing the method of the invention, the injection of the D₂ Osolution is arranged to take place while a patient is located within thefield of a NMR system magnet, so sequential H-1 images of the artery arethus immediately obtained. The solution may be injected into anysuitable artery or vein of the patient in an acceptable amount of D₂ Oto provide a desirably dark dye-like appearance of the D₂ O in thesequence of NMR images as the injected solution becomes diluted duringits movement through the coronary arteries.

To the extent that the diluted solution is visible in the myocardium,kidneys and other organs, it is useful for making various studies ofsuch organs. Relatively small doses of D₂ O have been found toconstitute such acceptable amounts for forming a desirably dark dye-likeNMR image. In one approach, an acceptable dosage of about 10 to 20milliliters of high purity D₂ O in water solution can be injected intothe coronary artery of a patient. In one experiment, a dosage of about100 to 200 milliliters of high purity D₂ O (at least 99% by weight D₂ O,in water) was injected into the renal artery of a dog and was found toprovide a suitably dark NMR image. That volume is relatively smallcompared to the total body water volume of a typical patient. That factand the fact that the D₂ O solution is made isotonic prior to itsinjection, results in the solution being found to exhibit no toxicityrelative to the patient.

A typical hospital type NMR system can be used to practice the method ofthe invention. For example, the 0.6 Tesla Technicare system located atNorth Shore Hospital in Manhasset, Long Island, N.Y. has been found tobe suitable for practicing the method of the invention. Another exampleof such a suitable system is the 1.5 Tesla GE system installed at CedarSinai Medical Center in Los Angeles, Calif.

EXAMPLE

An isosmotic solution of high purity D₂ O (about 99.81% by weight D₂ O,in H₂ O) was injected via a femoral catheter into the renal artery of ananesthestized dog while sequential H-1 images from a conventional (0.6Tesla) NMR imaging system were obtained. Because the D nuclei in thesolution emitted no signal at the frequency of the H-1 resonance, the D₂O was found to appear as a "dark dye" as it moved through the artery,undergoing dilution, when it proceeded into the kidney. This test showedclear images of the artery, the progressive dilution of the D₂ Osolution, and of the flow of the solution through the kidney.

We claim:
 1. A method for in vivo NMR imaging consisting of positioning a patient within the magnetic field of an energized NMR system, administering an acceptable NMR imaging amount of stable, high-purity D₂ O in isosmotic water solution by injecting the solution through a catheter into a blood vessel of the patient, said acceptable amount of D₂ O being sufficient to enable the administered D₂ O to form dark dye-like images as the solution is subjected to the H-1 resonance of the system, said H-1 resonance being effected at a frequency at which D₂ O will not resonate, detecting H-1 resonance signals, and processing said signals to provide an image.
 2. An NMR imaging method comprising using a dense solution of D₂ O and H₂ O as an imaging dye said dense solution of D₂ O and H₂ O having a ratio of D₂ O/H₂ O equal to at least 99.00% by weight D₂ O, causing H-1 resonance, detecting H-1 resonance signals, and processing said signals to provide an image. 